ISSN: 2349-8889 International Journal for Research in Applied Sciences and Biotechnology Volume-8, Issue-4 (July 2021) www.ijrasb.com https://doi.org/10.31033/ijrasb.8.4.11
Review on Parkinson’s Disease, a Neurodegenerative Disorder and The Role of Ceruloplasmin Protein in It
Ajay Chaudhary1, Noopur Khare2, Yamini Dixit3 and Abhimanyu Kumar Jha4 1Department of Biotechnology, Faculty of Life Sciences, Institute of Applied Medicines and Research, Ghaziabad, Uttar Pradesh, INDIA 2Shri Ramswaroop Memorial University, Barbanki, Uttar Pradesh, INDIA 3Department of Biotechnology, Faculty of Life Sciences, Institute of Applied Medicines and Research, Ghaziabad, Uttar Pradesh, INDIA 4Department of Biotechnology, Faculty of Life Sciences, Institute of Applied Medicines and Research, Ghaziabad, Uttar Pradesh, INDIA
3Corresponding Author: [email protected]
ABSTRACT neurodegenerative disease [Gitler et al., 2017]. Increasing Parkinson’s disease (PD), a neurodegenerative Age is the one of the most common risk factor associated disease is becoming major health concern mainly for elder with neurodegenerative disease, especially in case of people of age over 60 years. The main cause of PD is Alzheimer’s and Parkinson’s disease [Przedborski et al., permanent loss/death of dopaminergic nerve cells present in 2003]. In this study, main focus will be the cause of PD brain part called substantia nigra, which is responsible for and ceruloplasmin role in it. dopamine synthesis. MAO-B, monoamine oxidase B, regulates dopamine metabolism and increased activity of Parkinson’s disease MAO-B causes dopamine degradation which in turn Parkinson’s disease (PD) is the second most promotes the accumulation of glutamate and oxidative stress occurring disease after Alzheimer’s disease in elder with free radical liberation. Several factors like oxidative people over the age of 60 years and was first explained as stress, free radical formation, increased cholesterol, “shaky palsy” in 1817 by James Parkinson. The main mitochondrial dysfunction, nitric oxide toxicity, signal- cause of PD is the loss of dopaminergic nerve cells present mediated apoptosis, head trauma, and environmental toxins in brain part called substantia nigra where and gene mutations like VPS35, SNCA, EIF4G1, GBA, neurotransmitter dopamine is synthesized [DeMaagd and CHCHD, LRRK2, PINK1, DNAJC13 and SOD2 are associated with PD. Symptoms of PD include bradykinesia, Philip, 2015; Marino et al., 2020]. Monoamine oxidases muscle rigidity, resting tremors, postural instability and (MAO) discovered by Mary L.C. in 1928, regulates shuffling gait, constipation, sleep problems, fatigue, apathy, monoamine neurotransmitters levels and two isoforms: loss of smell and taste, excessive sweating, frequent MAO-A and MAO-B. MAO-B metabolizes dopamine nightmares, dream enacting behaviour, anxiety, depression, (DA) in substantia nigra and increased activity of MAO- daytime drowsiness. In PD, low levels of ceruloplasmin were B causes DA degradation which in turn promotes the observed in people with early onset of PD. Ceruloplasmin, a accumulation of glutamate and oxidative stress with free ferroxidase enzyme which is synthesized in liver radical liberation [Yeung et al., 2019; Marino et al., 2020]. parenchymal cell, regulates iron metabolism and lower level of which causes iron accumulation in brain which is Risk factors and Genetic Mutations responsible for the early onset of PD. Levodopa-based Risk factors and genetic mutations both are preparations, Dopamine agonists, Catechol-o- associated with PD. Some risk factors associated with PD methyltransferase (COMT) inhibitors, MOA-B inhibitors, are free radical formation, oxidative stress, elevated Adjunctive therapy, Antiglutamatergics drugs are currently cholesterol, mitochondrial dysfunction, nitric oxide used for the treatment of PD. toxicity, signal-mediated apoptosis, head trauma, and environmental toxins like Cyanide, Carbon disulphide, Keywords- Parkinson’s disease, Quercetin, Methanol and organic solvents, Pesticides and Herbicides Ceruloplasmin, Monoamine oxidase B (MAO-B) [DeMaagd and Philip, 2015]. Gene mutations associated with PD are VPS35, SNCA, EIF4G1, GBA, CHCHD, LRRK2, PINK1, I. INTRODUCTION DNAJC13 and SOD2 [DeMaagd and Philip, 2015; Marino et al., 2020]. Neurodegenerative disease, a permanent SNCA: A 14.5 kDa protein of 140 amino acids expressed loss/death of nerve cells is becoming a major concern for mainly in brain and also in heart, pancreas and skeletal human health, mostly for elderly people. Huntington’s muscle is thought to be involved in regulation of release disease, Parkinson’s disease, Amyotrophic lateral and transport of DA. In nondopaminergic neurons, it sclerosis, Spinocerebellar ataxias, Alzheimer’s disease inhibits the expression of p53 and transactivation of and frontotemporal dementia are all the examples of proapoptotic genes and provides a neuroprotective
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ISSN: 2349-8889 International Journal for Research in Applied Sciences and Biotechnology Volume-8, Issue-4 (July 2021) www.ijrasb.com https://doi.org/10.31033/ijrasb.8.4.11 phenotype but this neuroprotective effect is eliminated by III. CURRENT TREATMENT missense mutations in SNCA which causes apoptosis by METHODS FOR PD reversing the p53 expression [Siddiqui et al., 2016]. GBA: The gene, GBA encoding a lysosomal enzyme, No permanent cure for PD has been found yet glucocerebrosidase (GCase) which is involved in but a great deal of progress has been made for the glucosylceramide metabolism, is present in a gene rich treatment of PD. Some of the treatment [Stoker et al., region on chromosome 1 (1q21). A mutation in GCase 2018, Jankovic et al., 2008] currently used for PD are: makes it unable to fold properly causing its accumulation in dopaminergic neurons cellular compartments. 1. Levodopa-based preparations Accumulation of alpha synuclein (SNCA) is observed due 2. Dopamine agonists to impaired GCase activity [Riboldi et al., 2019; 3. Catechol-o-methyltransferase (COMT) inhibitors Sidransky and Lopez, 2014]. 4. MOA-B inhibitors Symptoms of PD 5. Adjunctive therapy PD symptoms can be classified in two 6. Antiglutamatergics drugs categories: Motor symptoms and Non-motor symptoms. Motor Symptoms: Lag in movement initiation Deep brain stimulation (DBS), a safe treatment (bradykinesia), muscle rigidity, resting tremors, postural method for PD which could be efficacious in improving instability, speech disturbances, dystonia (sustained the movement disorder [Stoker et al., 2018]. muscular contraction) and shuffling gait are some motor symptoms [Fritsch et al., 2012; Sveinbjornsdottir 2016]. IV. CONCLUSION Non-Motor Symptoms: Constipation, sleep problems, fatigue, apathy, loss of smell and taste, excessive Even though PD is the second most common sweating, frequent nightmares, dream enacting behaviour, neurodegenerative disease after Alzheimer’s disease, still anxiety, depression, daytime drowsiness are some non- it poses a major health concern for elder people and no motor symptoms of PD [Fritsch et al., 2012; cure has yet been found for it. Several treatments are Sveinbjornsdottir 2016]. proved to be very efficient for PD among which Levodopa being a better option than others but long time treatment II. ROLE OF CERULOPLASMIN IN with levodopa is not recommended because of its side PARKINSON’S DISEASE effects. Several factors and mutations are associated with PD but main cause is the iron accumulation and oxidative Ceruloplasmin, encoded by CP gene in humans stress due to free radical formation in nerve cells. This is a ferroxidase enzyme which is synthesized in liver study mainly focussed the cause and current treatments used for PD. parenchymal cell and member of multicopper oxidase family. It is a major carrier of copper in blood (90-95% of copper) which is added by the P-type ATPase after its REFERENCES synthesis. Copper is required by ceruloplasmin for its proper folding. The molecular weight of ceruloplasmin is [1] Bharucha K. J., Friedman J. K., Vincent A. S., Ross 132 kDa and it is composed of three asparagine-linked E. D. Lower Serum Ceruloplasmin Levels Correlate with oligosachharides and a polypeptide chain of size 1046 Younger Age of Onset in Parkinson’s Disease. J. Neurol. amino acids [Lopez et al., 2021, Gaware et al., 2010, 2008 255(12):1957-1962. Hellman et al., 2002] [2] DeMaagd G., Philip A. Parkinson’s Disease and Its Ceruloplasmin is a redox reaction catalyst and it Management. Pharm. Ther. 2015 40(8):504-510. regulates iron metabolism i. e. the oxidation of iron from [3] Fritsch T., Smyth K. A., Wallendal M. S., Hyde T., ferrous (fe2+) to ferric iron (fe3+) which helps in iron Leo G., Geldmacher D. S. Parkinson Disease: Reasearch binding to transferrin [Lopez et al., 2021]. Transferrin is Update and Clinical Management. South. Med. J. 2012 a glycoprotein found in blood plasma that has high 105(12): 650-656. affinity to ferric iron. It carries iron to various tissue such [4] Gaware V., Kotade K., Dhamak K., Somawanshi S. as spleen, liver and bone marrow [Ogun et al., 2020]. Ceruloplasmin Its Role and Significance: A Review. Int. In Parkinson’s disease lower level of J. Biomed. Res. 2010 1(4): 153-162. ceruloplasmin has been observed in people with early [5] Gitler A. D., Dhillon P., Shorter J. onset of PD. Mutation in ceruloplasmin gene causes the Neurodegenerative Disease: Models, Mechanisms and a absence or low level of ceruloplasmin. Accumulation of New Hope. Dis. Model Mech. 2017 10(5): 499-502. [6] Hellman N. E., Gitlin J. D. Ceruloplasmin iron occurs in the liver, brain and pancreas due to the Metabolism and Function. Annu. Rev. Nutr. 2002 22: 439- absence of ferroxidase activity which causes damage to 458. the tissues by the formation of free radicals [Bharucha et al., 2008, McNeill et al., 2008]
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